Cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-9381256-B2
Application number	US-201514843604-A
Country	US
Kind code	B2
Filing date	Sep 2, 2015
Priority date	Sep 3, 2014
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VII). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

First claim

We claim:

1. A compound represented by any one of the following formulas:

or a pharmaceutically acceptable salt thereof, wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H, or an amine protecting group;
Y is selected from —H, —OR, —OCOR′, —SR, —NR′R″, —SO 3 M, —SO 2 M or —OSO 3 M, wherein M is —H or a cation;
R is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH 2 CH 2 O) n —R c , wherein n is an integer from 1 to 24, and R c is a linear or branched alkyl having 1 to 4 carbon atoms;
R′ and R″ are the same or different, and are selected from —H, —OR, —NRR g′ , —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted aryl having from 6 to 18 carbon atoms, an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, a PEG group —(CH 2 CH 2 O) n —R c , wherein n is an integer from 1 to 24, preferably n is 2, 4 or 8; and R g′ is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH 2 CH 2 O) n —R c ;
X′ is selected from the group consisting of —H, —OH, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, phenyl, and an amine-protecting group;
Y′ is selected from the group consisting of —H, an oxo group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
R′ is a linear or branched alkylene having 1 to 6 carbon atoms, optionally substituted with a charged substituent or an ionizable group Q;
R e is —H or a linear or branched alkyl having 1 to 6 carbon atoms;
G is selected from —CH— or —N—;
Z s is —H, —SR d , or is selected from any one of the following formulas:

wherein:
q is an integer from 1 to 5;
R d is a linear or branched alkyl having 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl;
n′ is an integer from 2 to 6;
U is —H or —SO 3 M; and
M is —H or a cation.

2. The compound of claim 1 , wherein R e is —H or -Me.

3. The compound of claim 2 , wherein R x is —(CH 2 ) p —(CR f R g )—, wherein R f and R g are each independently selected from —H or a linear or branched alkyl having 1 to 4 carbon atoms; and p is 0, 1, 2 or 3.

4. The compound of claim 2 , wherein R x is a linear or branched alkylene having 1 to 4 carbon atoms substituted with a charged substituent or an ionizable group Q.

5. The compound of claim 3 , wherein the double line between N and C represents a double bond.

6. The compound of claim 3 , wherein the double line between N and C represents a single bond; X is —H or an amine protecting group and Y is selected from —H, —SO 3 M, —OH, —OMe, —OEt or —NHOH.

7. The compound of claim 1 , wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —H, and when it is a single bond, X is —H; Y is —OH or —SO 3 M;
M is —H or a pharmaceutically acceptable cation;
X′ and Y′ are both —H; and
G is C.

8. The compound of claim 1 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein M is H + , Na + or K + .

9. A conjugate comprising a cytotoxic compound and a cell-binding agent (CBA), wherein the cytotoxic compound is covalently linked to the CBA, and wherein said cytotoxic compound is represented by any one of the following formulas:

or a pharmaceutically acceptable salt thereof, wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H, or an amine protecting group;
Y is selected from —H, —OR, —OCOR′, —SR, —NR′R″, —SO 3 M, —SO 2 M or —OSO 3 M, wherein M is —H or a cation;
R is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH 2 CH 2 O) n —R c , wherein n is an integer from 1 to 24, and R c is a linear or branched alkyl having 1 to 4 carbon atoms;
R′ and R″ are the same or different, and are selected from —H, —OR, —NRR g′ , —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted aryl having from 6 to 18 carbon atoms, an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, a PEG group —(CH 2 CH 2 O) n —R c , wherein n is an integer from 1 to 24, preferably n is 2, 4 or 8; and R g′ is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl ha

Assignees

• Immunogen Inc

Inventors

• Chari Ravi V J
• Miller Michael Louis
• Shizuka Manami

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/04

  Antibacterial agents · CPC title